EP0190676B1 - All-cis-1,3,5-Triamino2,4,6-cyclohexantriol-Derivate, ihre Verwendung, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Präparate - Google Patents

All-cis-1,3,5-Triamino2,4,6-cyclohexantriol-Derivate, ihre Verwendung, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Präparate Download PDF

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Publication number
EP0190676B1
EP0190676B1 EP86101269A EP86101269A EP0190676B1 EP 0190676 B1 EP0190676 B1 EP 0190676B1 EP 86101269 A EP86101269 A EP 86101269A EP 86101269 A EP86101269 A EP 86101269A EP 0190676 B1 EP0190676 B1 EP 0190676B1
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EP
European Patent Office
Prior art keywords
alkyl
derivatives
cis
ppm
cyclohexanetriol
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Expired
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EP86101269A
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German (de)
English (en)
French (fr)
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EP0190676A1 (de
Inventor
Walter Prof. Dr. Anorganische Chemie Schneider
Isidor Dr. Sc.Nat. Anorganische Chemie Erni
Hans K. Dr. Sc.Nat. Anorganische Hegetschweiler
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Vifor International AG
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Laboratorien Hausmann AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/383—Cycloaliphatic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton

Definitions

  • the present invention relates to new all-cis-1,3,5-triamino-2,4,6-cyclohexanetriol derivatives, which are also referred to as cis-1,3,5-triamino-1,3,5-trideoxy-inositol are, processes for their preparation, pharmaceutical preparations containing these derivatives and / or the known base, the all-cis-1,3,5-triamino-2,4,6-cyclohexanetriol, and the use of these derivatives and Basic body for the manufacture of medicaments for therapeutic use in the case of iron overload in the animal and in particular the human body.
  • the invention also relates to the use of the above-mentioned derivatives (ligands) for dissolving other undesirable iron deposits.
  • the invention also relates to the use of the above-mentioned ligands for other metal ions, in particular as ion carriers in ion-selective electrodes (cf. “lon-selective electrodes”, Cambridge University Press, Cambridge, [1983]) or in therapeutic or diagnostic Applications (cf. Inorganic Chemistry in Biology and Medicine, ACS Symposium Series 140, American Chemical Society, Washington, DC [1980] pp. 121 to 140, 91 to 101 and 103 to 119).
  • Iron is widespread in biological systems and takes part in important biochemical reactions.
  • the body of a healthy adult human contains about 4 g of iron. More than half of it (about 2.6g) is found in the hemoglobin in the red blood cells.
  • Iron deficiency is relatively widespread, but serious health problems are rare. Iron overload is observed much less often, but the health effects are significantly more severe.
  • the only way the body can excrete iron is to reject cells (skin flakes, exfoliated cells of the intestinal wall) and to lose blood. Excess iron can first be stored in special depots. If the capacity is exceeded, iron begins to have a toxic effect. The pathological condition achieved in this way is called hemochromatosis or hemosiderosis.
  • iron hydroxide deposits can be delayed by the administration of complexing agents (ligands) which are able to remove the iron from the body in a soluble form.
  • complexing agents ligands
  • it is known to administer 30-amino-3,14,25-trihydroxy-3,9,14,20, 25-pentaaza-2,10,13,21,24-triacontanepentaonemethanesulfonate- (deferoxamine) cf. FR 694M and Inorganic Chemistry in Biology and Medicine, ACS Symposium Series 140, American ChemiceJ - Society, Washington, DC [1980], pp. 279 to 312).
  • the new compounds according to the invention have a relatively low toxicity and can be administered intravenously or in some cases also orally.
  • the above-mentioned known basic structure of the new compounds according to the invention which has not hitherto been recommended as a pharmaceutical, also has a relatively low toxicity and also has a good effect on dissolving iron by complex formation.
  • the invention accordingly also relates to pharmaceutical preparations which contain the all-cis-1,3,5-triamino-2,4,6-cyclohexanetriol or compounds of the formulas 1 to VI as claimed in claim 1 as an active ingredient, optionally together with customary pharmaceutical diluents , Additives or excipients.
  • the compounds used according to the invention are advantageously used per dose in an amount of 1 to 50 mg of active ingredient per kilogram of body weight.
  • 1-10 mg / kg are sufficient, for acute detoxification up to 50 mg / kg can be given.
  • the compounds can be formulated in a customary manner into pharmaceutically usable administration forms.
  • 1,3,5-Triamino-2,4,6-cyclohexanetriols can exist in ten different diastereomeric forms with regard to the position of the nitrogen and oxygen atoms.
  • the so-called all-cis-1,3,5-triamino or -trialkylamino-2,4,6-cyclohexanetriol of the formula according to the invention is of interest, which can be represented in simplified form as follows.
  • the invention thus relates to a production process in which phloroglucin (5) with acetic anhydride is converted virtually quantitatively into the triacetate (9) by the method of Heller, reports 45, 421 (1912). Protected in this way, nitration according to Nietzki and Moll, Reports 26, 2185-2187 (1893), can be carried out safely in smoking nitric acid.
  • the resulting, moderately water-soluble tripotassium salt can, for. B. precipitated as a sparingly soluble barium salt and can easily be obtained in this form in pure form.
  • the addition of a stoichiometric amount of acid e.g. Sulfuric acid then releases the desired trinitrophloroglucin (4).
  • the trinitrophloroglucin is then hydrogenated. This means that the previously required isolation of the extremely oxygen-sensitive triaminophloroglucine can be dispensed with without sacrificing purity and yield.
  • the monoalkali metal salt, in particular the potassium salt, can also be used instead of the free phenol (4).
  • the hydrogenation is carried out with vigorous stirring which creates turbulence.
  • a mixture of various polyhydroxypolyamino-cyclohexanes is obtained, from which the desired all-cis-1,3,5-triamino-2,4,6-cyclohexanetriol as a salt, e.g. as sulfuric acid salt (10a) by repeated recrystallization, e.g. can be isolated from water-methanol.
  • Different salts can be prepared, for example, by ion exchange on an anion exchange resin from the primarily obtained sulfate (10a), e.g. B. the trichloride (10b), the triformate (10c) or the free base (1).
  • sulfate (10a) e.g. B. the trichloride (10b), the triformate (10c) or the free base (1).
  • a stoichiometric reaction of the sulfate (10a) with barium hydroxide can take place, which also leads to (1).
  • the free amine or its salt can be alkylated or acylated.
  • the usual agents suitable for the alkylation or acylation of amines can be used.
  • alkylating agents are alkyl halides (e.g. bromides and iodides) having 1 to 18 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl and tert-butyl iodide or -bromide).
  • alkyl halides e.g. bromides and iodides
  • olefins and alcohols that can be used for addition or condensation for alkylation are olefins with 1 to 18 carbon atoms (e.g. those with activating substituents, such as nitrile functions, e.g. acrylonitrile) and alcohols with 1 to 18 carbon atoms (e.g. B. those with activating substituents such as nitrile function, e.g. glycolic acid nitrile). Reductive alkylation with aldehydes and ketones with 1 to 18 carbon atom
  • acylating agents are reactive derivatives of alkanoic acids with 1 to 18 carbon atoms in the alkyl part, such as acid halides, especially acid chlorides, acid anhydrides and esters. Specific examples are acetyl chloride, propionyl chloride, caprylic acid chloride and succinic anhydride.
  • the alkylating and acylating agents can be substituted by one or more identical or different functional groups or their precursors, in particular those which can coordinate with metal cations, in particular iron (III).
  • Such functional groups can be in protected form, especially when there is a risk that they will be influenced or interfere in the reaction under the chosen alkylation or acylation conditions.
  • substituents are: hydroxyl groups, carboxyl groups (and their derivatives, such as salts, amides and esters and the nitrile group as their precursors), -CON (OH) R, where R is an alkyl group having 1 to 6, in particular 1 to 4, carbon atoms is -OP0 3 H or its salts and esters, -P0 3 H or its salts and esters, -SR, wherein R is as defined for -CON (OH) R, and-CN, and and or and / or their salts.
  • the all-cis-1,3,5-triamino-2,4,6-trihydroxycyclohexane compounds in the form of their quaternized derivatives (for example of the formula II) with the corresponding difunctional alkylating agents, e.g. Alkylene halides, e.g. B. methylene or ethylene halides (z. B. bromides or iodides) are implemented. It is preferably carried out in the presence of strong bases, such as alcoholates, for example alkali metal and / or alkaline earth metal methoxide or ethoxide in the corresponding alcohol as solvent.
  • the diamine derivatives of the general formula IV are prepared by alkylating the all-cis-1,3,5-triamino-2,4,6-trihydroxycyclohexane derivatives of the general formula with a difunctional alkylating agent, e.g. B. alkylene halides with 4 to 8 methylene groups.
  • a difunctional alkylating agent e.g. B. alkylene halides with 4 to 8 methylene groups.
  • complexes of two molecules thereof with iron (III) or chromium (III) can also be used.
  • alkylation of the free amines or their salts generally leads to secondary when using alkylating agents with short-chain alkyl radicals, in particular the methyl radical Amines; it can continue until quaternization.
  • alkylating agents are used to introduce longer-chain, secondary or tertiary alkyl groups and to introduce alkyl groups with bulky substituents, the corresponding primary amine derivatives are generally obtained.
  • the alkylated products obtained can be quaternized by alkylation.
  • alkyl halides for example methyl, ethyl, propyl, isopropyl, butyl halides (for example iodides, bromides and chlorides) according to the following scheme leads to the corresponding mono-, di- and triquaternary products.
  • the tri-quaternary iodide (19a) can be obtained from the resulting mixtures by recrystallization e.g. separate from weakly alkaline aqueous solution of (17) and (18).
  • Triquaternization is e.g. B. also possible in alkaline aqueous solution of all-cis, 1,3,5-tris (dimethylamino) -2,4,6-cyclohexanetriol with an excess of bromohydrins or epoxides (z. B. bromoethanol or ethylene oxide) .
  • the pH is preferably regulated to a value of about 10 by adding alkali.
  • Suitable pharmaceutically acceptable salts of the compounds according to the invention are those with an organic acid (e.g. an acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate) or with an inorganic acid (e.g. chloride, bromide, sulfate, phosphate).
  • an organic acid e.g. an acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate
  • an inorganic acid e.g. chloride, bromide, sulfate, phosphate
  • compositions according to the invention can, for example, be solid or liquid and can be in pharmaceutical forms, as are usually used in human medicine or veterinary medicine, such as, for. B. as simple or coated tablets, yellow capsules, capsules, granules, Suppositories and injectable preparations. They are manufactured using standard methods.
  • the active ingredient (s) can be incorporated into such pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fat bodies of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants - or emulsifiers and preservatives.
  • metal ions for which, as mentioned above, the compounds according to claim 1 and / or the all-cis, 1,3,5-triamino-2,4,6-cyclohexanetriol can be used are alkaline earth metal ions, in particular magnesium, however also calcium, strontium, barium. Other examples are the rare earth ions, particularly gadolinium. Another group of ions are those of aluminum, gallium, indium or technetium.
  • the ligands used according to the invention form particularly light and particularly stable and / or particularly readily soluble complex compounds with these metals. On the other hand, the aforementioned metals are of great importance in the fields of application mentioned above.
  • the solid is centrifuged off and the supernatant solution is filtered through a suction filter coated with Celite.
  • the residue is reslurried in water and the procedure described repeated until the supernatant solution is practically colorless after centrifuging (2-3 times)
  • the combined filtrates are concentrated to 100 ml on a rotary evaporator at a bath temperature of 30-40 ° C., a yellow solid precipitating out.
  • the suspension is transferred to a 1 liter pear flask and heated to 98 ° C on a water bath. Add small amounts of water until everything is dissolved, filter the hot solution through a nutsche preheated with a hair dryer and slowly cool to 4 ° C.
  • Trinitro-phloroglucin hydrate crystallizes in large, yellow needles, which are separated from the mother liquor on a suction filter and dried in a water jet vacuum at room temperature.
  • the autoclave is now opened and 47 g (168 mmol) of solid trinitrophloroglucin are added.
  • the suspension is hydrogenated with cooling and vigorous stirring at a hydrogen pressure of 10 bar.
  • the first stage reduction of the nitro groups
  • the second stage hydrolysis of the aromatics
  • cooling is no longer necessary.
  • the end of the first stage can be recognized by the disappearance of the yellow color.
  • the reduction time depends heavily on the intensity of stirring.
  • the specified reaction time relates to a mechanically driven agitator with a stirring speed of 1200 rpm. A white solid will fall out over time.
  • the reaction is stopped and the suspension is transferred to a 51 round-bottom flask. It is diluted with water to a volume of 3.51 and stirred until the white solid has completely dissolved.
  • the catalyst is separated off using a G4 filter and the practically colorless filtrate is concentrated to 500 ml on a rotary evaporator. 1 M sulfuric acid is added to the suspension until a pH of approximately 2 has been established. 1.21 of methanol are added, the suspension is left to stand at 4 ° C. for at least 12 h and is filtered off with suction.
  • the product is recrystallized 6 times as follows: water (25.degree. C.) is dissolved in the minimal amount (approx. 1.61), filtered through a G4 suction filter and the solution is slowly mixed with 750m) of methanol while stirring. The suspension is left overnight at 4 ° C. and the solid is separated off from the mother liquor using a suction filter. The product is first dried in a drying cabinet at 80 ° C, then in a vacuum at 0.01 Torr and 80 ° C to constant weight.
  • the yield is 27 g (84 mmol). This corresponds to 50% with respect to the trinitrophloroglucin used.
  • the required platinum dioxide hydrate can, for example, each time be prepared from ammonium hexachloroplatinate (IV) according to a modified Org. Syntheses specification (Adams 1964) before the reaction: A mixture of 100 g sodium nitrate and 8 g ammonium hexachloroplatinate is weighed into a 250 ml Pyrex beaker (the use of potassium nitrate described in Org. Syntheses [1964] causes the beaker to crack during the reaction). The mixture is heated in a chapel in an open crucible furnace. The temperature can be checked with a calibrated Chromel-Alumel thermocouple (Handbook 1974). The mixture turns brown and lively gas evolution occurs under melting.
  • Foaming and splashing can be prevented by stirring with a glass rod.
  • reaction mixture must not come into contact with apparatus parts made of (stainless) steel, otherwise the iron, which has been dissolved by corrosion, will be complexed with the resulting product during the reaction. These metal complexes are difficult to separate afterwards.
  • the filtrate is evaporated to dryness on a rotary evaporator, dissolved in 100 ml of water and placed on an ion exchange column Dowex 1, CI shape (column dimension: length 30 cm, diameter 3 cm; ion exchange resin: Dowex 1, X 4. 50/100 mesh, chloride form; activation and regeneration: elute with 21 2M HCI, then with water until the eluate reacts neutral). Elute until the filtrate is free of chloride and test for sulfate with dilute barium chloride solution. If barium sulfate precipitation can be observed, the ion exchange must be repeated on a regenerated column.
  • the mixture is left to stand at 4 ° C. for 24 hours.
  • a colorless solid crystallizes, which is recrystallized again from 150 ml of boiling hexane.
  • the product is filtered off with suction and dried to constant weight at 0.01 Torr and room temperature.
  • the sulfate (12b) was obtained by stoichiometric reaction of the amine (11) with dilute sulfuric acid. In contrast to chloride (12a), it is practically insoluble in boiling methanol.
  • the quaternization was carried out in methanol, acetonitrile and nitromethane at room temperature or under reflux.
  • the tri-quaternary compound was obtained in pure form by recrystallization.

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EP86101269A 1985-02-02 1986-01-31 All-cis-1,3,5-Triamino2,4,6-cyclohexantriol-Derivate, ihre Verwendung, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Präparate Expired EP0190676B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT86101269T ATE41654T1 (de) 1985-02-02 1986-01-31 All-cis-1,3,5-triamino2,4,6-cyclohexantriolderivate, ihre verwendung, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische praeparate.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3503614 1985-02-02
DE19853503614 DE3503614A1 (de) 1985-02-02 1985-02-02 All-cis-1,3,5-triamino-2,4,6-cyclohexantriol-derivate, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische praeparate

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EP0190676A1 EP0190676A1 (de) 1986-08-13
EP0190676B1 true EP0190676B1 (de) 1989-03-22

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EP86101269A Expired EP0190676B1 (de) 1985-02-02 1986-01-31 All-cis-1,3,5-Triamino2,4,6-cyclohexantriol-Derivate, ihre Verwendung, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Präparate

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US (1) US4794197A (ko)
EP (1) EP0190676B1 (ko)
JP (1) JP2519205B2 (ko)
KR (1) KR900006133B1 (ko)
AR (1) AR242177A1 (ko)
AT (1) ATE41654T1 (ko)
AU (1) AU589156B2 (ko)
CA (1) CA1289963C (ko)
DE (2) DE3503614A1 (ko)
ES (1) ES8704446A1 (ko)
GR (1) GR860301B (ko)
IN (1) IN166368B (ko)
PT (1) PT81955B (ko)

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CH679742A5 (ko) * 1990-01-09 1992-04-15 Byk Gulden Lomberg Chem Fab
DE4028139A1 (de) * 1990-09-05 1992-03-12 Hausmann Ag Labor Verwendung der komplexe radioaktiver metallionen mit all-cis-1,3,5-triamino-2,4,6-cyclohexantriol und seinen derivaten fuer roentgendiagnostische zwecke und in der tumortherapie sowie zur herstellung von mitteln fuer roentgendiagnostische zwecke und fuer die tumortherapie
US5563328A (en) 1992-08-19 1996-10-08 Board Of Regents, University Of Nebraska-Lincoln Promoters from chlorella virus genes providing for expression of genes in prokaryotic and eukaryotic hosts
US6673537B1 (en) 1992-08-19 2004-01-06 Board Of Regents, University Of Nebraska-Lincoln Promoters from chlorella virus genes providing for expression of genes in prokaryotic and eukaryotic hosts
FR2779711B1 (fr) * 1998-06-12 2000-07-07 Commissariat Energie Atomique Procede de separation des cations lanthanides trivalents par complexation selective
US7057073B2 (en) * 2003-08-04 2006-06-06 Regents Of The University Of California Synthesis of trinitrophloroglucinol and triaminotrinitrobenzene (TATB)
CN104321082A (zh) 2012-05-18 2015-01-28 拜耳医药股份有限公司 用于x射线成像的双氮杂肌醇重金属络合物
EP2796152A1 (en) 2013-04-25 2014-10-29 Bayer Pharma Aktiengesellschaft Unsymmetrical Bis Azainositol Hafnium Complexes for X-Ray Imaging
EP2873670A1 (en) 2013-11-14 2015-05-20 Bayer Pharma Aktiengesellschaft Bis azainositol zirconium complexes for X-ray imaging

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Publication number Priority date Publication date Assignee Title
FR694E (fr) 1901-07-16 1903-02-25 Megy Leandre Une nouvelle automobile
FR1522204A (fr) * 1963-01-21 1968-04-26 Upjohn Co Actinamine et ses dérivés et leur procédé de fabrication
US3496196A (en) * 1965-10-02 1970-02-17 Tanabe Pharm Co Ltd 4,6-diazido-4,6-dideoxy-myo-inositol tetraacylates
DE2360176A1 (de) * 1973-12-03 1975-06-05 Basf Ag Verfahren zur herstellung von 2,4,6- substituierten cyclohexan-1,3,5-triolen
DE2537682C2 (de) * 1975-08-23 1984-02-02 Basf Ag, 6700 Ludwigshafen Epoxy-cyclohexen - Derivate

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ATE41654T1 (de) 1989-04-15
ES551485A0 (es) 1987-04-16
DE3503614C2 (ko) 1987-11-26
EP0190676A1 (de) 1986-08-13
ES8704446A1 (es) 1987-04-16
AU589156B2 (en) 1989-10-05
CA1289963C (en) 1991-10-01
DE3662520D1 (en) 1989-04-27
PT81955A (en) 1986-03-01
GR860301B (en) 1986-06-02
IN166368B (ko) 1990-04-21
PT81955B (pt) 1988-07-01
KR900006133B1 (ko) 1990-08-24
JP2519205B2 (ja) 1996-07-31
KR860006432A (ko) 1986-09-11
US4794197A (en) 1988-12-27
DE3503614A1 (de) 1986-08-07
JPS61210058A (ja) 1986-09-18
AR242177A1 (es) 1993-03-31
AU5285986A (en) 1986-10-16

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